I. What every physician needs to know.

In the normal physiologic state, the pancreas secretes about 1.5 liters of fluid daily that contains enzymes needed for digestion of fats, protein, and carbohydrates. The secretion of this fluid is controlled by hormonal (i.e. secretin, cholecystokinin) and neuronal signals.

Exocrine pancreatic insufficiency occurs when there is inadequate production of these digestive enzymes due to structural damage of the pancreas, dysregulation of the hormonal or neuronal signals, or inappropriate inactivation of the enzymes. The most common causes of pancreatic insufficiency are chronic pancreatitis in adults and cystic fibrosis in children. Additional causes include prior surgery (i.e. gastric, pancreatic, or small bowel resections), pancreatic duct obstruction (i.e. malignancy, cystic neoplasm, pancreas divisum, pancreatic duct stone), autoimmune pancreatitis, short bowel syndrome, celiac disease, Shwachman-Diamond syndrome, alpha-1 antitrypsin deficiency and hemochromatosis.

The gold standard for quantification of pancreatic function is a secretin-stimulated test; however it is invasive, costly, and not available universally. The best test for quantification of steatorrhea is the 72 hour fecal fat quantification though it is cumbersome for patients to collect and not reliable in milder cases of pancreatic insufficiency. Thus, the diagnosis is often dependent on an accurate history with suspicion for pancreatic insufficiency. The fecal elastase test has become the most widely used and accepted test for diagnosis. Some clinicians may empirically start patients on pancreatic enzyme replacement therapy and monitor for response as an indirect means of diagnosing the patients with pancreatic exocrine insufficiency.

A. History Part I: Pattern Recognition:

Patients with mild exocrine pancreatic insufficiency generally have no symptoms and normal bowel movements though some may report mild bloating or abdominal discomfort. In more advanced cases, patients begin to develop symptoms due to fat and protein maldigestion. These patients often have steatorrhea with foul-smelling, high volume fatty stools, chronic abdominal pain, bloating, and weight loss. Steatorrhea typically does not occur until 90% of the pancreatic function has been compromised.

Due to the malabsorption that occurs, patients are at higher risk to develop deficiencies of fat soluble vitamins (A, D, E and K), magnesium, calcium, zinc and folic acid. These nutrient deficiencies rarely result in symptoms such as tetany, glossitis, peripheral neuropathy and osteoporosis.

Chronic pancreatitis is the most common cause of pancreatic exocrine insufficiency in adult patients. The estimated prevalence of pancreatic insufficiency is 35-50% in patients within 10-15 years of developing chronic pancreatitis. An estimated 87% of patients with autoimmune pancreatitis will develop pancreatic insufficiency.

C. History Part 3: Competing diagnoses that can mimic Pancreatic Insufficiency.

While the differential diagnosis includes all causes of diarrhea which is an exhaustive list, the main causes to consider in patients with steatorrhea are any alternative causes of fat malabsorption, including small intestinal bacterial overgrowth, celiac disease, giardiasis, and Zollinger-Ellison syndrome.

D. Physical Examination Findings.

Many patients with pancreatic exocrine insufficiency will have a normal physical exam. As the severity worsens without treatment, patients may have evidence of malnutrition and vitamin deficiencies.

Severe Vitamin D and calcium deficiency can result in signs of hypocalcemia like tetany, Trousseau and Chvostek sign.

Vitamin A deficiency can result in follicular hyperkeratosis and night blindness.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Direct testing of pancreatic function

Measuring pancreatic function directly it the most sensitive test for exocrine pancreatic insufficiency but the test is cumbersome and not universally available. The pancreas is stimulated by administering hormones (secretin and/or cholecystokinin) and collecting the pancreatic secretory fluid into the duodenum. The collected fluid is then analyzed for pancreatic enzymes (in response to cholecystokinin) and bicarbonate (in response to secretin) levels.

Under a similar principle, secretin-enhanced magnetic resonance imaging is used to estimate the volume of fluid secreted by the pancreas after administration of secretin.

Indirect testing of pancreatic function

Fecal tests: Of all the indirect tests available, fecal elastase if the most sensitive and specific. Fecal elastase is an enzyme that is secreted by the pancreas and remains stable until is excreted. The normal level is > 200 μg/g. It is 63% sensitive in mild disease and 100% sensitive in moderate to severe disease. The test is performed on a single stool sample and does not require discontinuation of enzyme replacement if the patient is already on therapy. False positive results may occur in patients with liquid stools due to the dilutional effect.

Similar to elastase, fecal chymotrypsin is also an enzyme secreted by the pancreas. However, it is less sensitive (49% in mild disease and 85% in severe disease) and specific than elastase test. Pancreatic enzyme replacement therapy contains chymotrypsin so therapy must be discontinued for 2 days before the test to improve accuracy. False positive results may also occur with liquid stools.

Qualitative evaluation of fat in stool using Sudan stain is nonspecific and should be avoided. Quantitative evaluation of fecal fat is a cumbersome test and rarely ordered since it requires a 72 hour stool collection and patients must follow consume 100 gm fat per day. Excretion of more than 7 gm/day of fat is diagnostic of fat malabsorption.

Blood tests: Serum trypsinogen is a measure of pancreatic acinar cell mass. While it is an inexpensive test to obtain, the sensitivity is high for severe pancreatic insufficiency only if levels are less than <20 ng/ml. False negative results may occur in the setting of acute pancreatic inflammation.

Breath tests: The 13C-MTG breath test measures the 13CO2 in breath sample after ingestion of 13C-marked substrates which are hydrolyzed by pancreatic lipase, absorbed in the intestine and ultimately released across the pulmonary endothelium. This test is not currently approved in the United States for diagnostic purposes.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Other than the aforementioned secretin-enhanced MRI, no other imaging is able to diagnose exocrine pancreatic insufficiency. However, results on imaging studies may be able to provide information to determine the underlying etiology in a patient once the diagnosis has been made. Pancreatic calcifications may be seen on plain x-rays or cross-sectional imaging. If the patient has unexplained weight loss or an underlying cause for pancreatic insufficiency has not been found, then MRI with cholangiopancreatography (MRCP) should be obtained to evaluate for structural abnormalities (e.g., malignancy, pancreatic duct obstruction).

Endoscopic ultrasound (EUS) may be able to diagnose early signs of chronic pancreatitis or identify structural abnormalities. ERCP may be used if there is evidence of pancreatic duct disruption or blockage.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

Pancreatic insufficiency may be a clinical diagnosis based on historical information. Stool studies (fecal elastase) is the most sensitive and specific test that is widely available and cost-effective. Imaging is not necessary for diagnosis but may be needed if there is suspicion for malignancy.

III. Default Management.

The goals of treatment are:

1. Optimize nutrition.

2. Control symptoms like diarrhea and bloating.

3. Correction of vitamin deficiencies.

A. Immediate management.

In patients with pancreatic insufficiency and evidence of malabsorption or steatorrhea typically require an equivalent of 70,000-100,000 lipase units per meal to resolve symptoms. This dose may vary based on the patient's weight, severity of pancreatic insufficiency, and fat content of each meal. Half of the dose should be taken with the first bite of the meal and remaining half midway through the meal to allow proper mixing of the enzymes with the food.

Malabsorption that occurs with pancreatic insufficiency causes and increased risk of vitamin deficiencies (A, D, E, K, B12) and should be checked at the time of diagnosis with supplementation as needed.

B. Physical Examination Tips to Guide Management.

Adjusting the doses of pancreatic enzyme replacement therapy can be done based on the patient’s symptoms. However, fecal elastase levels also can be used to monitor for effectiveness of therapy.

D. Long-term management.

Once the appropriate dose of pancreatic enzyme replacement has been identified, patients typically do well; however, yearly labs should be obtained to identify vitamin deficiencies and ensure therapy is adequate.

E. Common Pitfalls and Side-Effects of Management.

Pancreatic enzymes are typically well tolerated with little to no side effects. The most common side effects reported include headache, abdominal discomfort, nausea, bloating, hypersensitivity, and constipation.

Fibrosing colonopathy is a very rare entity that has been reported in children with cystic fibrosis on very high doses of enzymes over a long period of time.

A. Renal Insufficiency.

Contain purines which may increase uric acid concentration. No change in dose recommended.

B. Liver Insufficiency.

No change in standard management.

C. Systolic and Diastolic Heart Failure.

No change in standard management.

D. Coronary Artery Disease or Peripheral Vascular Disease.

No change in standard management.

E. Diabetes or other Endocrine issues.

Patients with exocrine pancreatic insufficiency often also have concomitant endocrine pancreatic insufficiency. All patients identified should also be screened for diabetes or glucose intolerance.

F. Malignancy.

No change in standard management.

G. Immunosuppression (HIV, chronic steroids, etc).

Though data is limited, there have been reports to suggest a higher incidence of pancreatic insufficiency in HIV patients, either due to the primary disease process or as a result of antiretroviral drugs.

H. Primary Lung Disease (COPD, Asthma, ILD).

No change in standard management.

I. Gastrointestinal or Nutrition Issues.

This is the treatment for pancreatic insufficiency.

J. Hematologic or Coagulation Issues.

No change in standard management.

K. Dementia or Psychiatric Illness/Treatment.

No change in standard management.

A. Sign-out considerations While Hospitalized.

If the patient's symptoms do not improve on pancreatic enzyme replacement therapy, the dose can be titrated until benefit is seen. In patients with ongoing weight loss or symptoms despite adequate therapy and compliance, imaging should be considered to rule out malignancy.

As the primary cause of pancreatic insufficiency is chronic pancreatitis, and one of the major causes of pancreatitis is alcohol abuse, patient should be screened for evidence of ongoing use. Those patient will need to be monitored closely for withdrawal symptoms.

B. Anticipated Length of Stay.

Pancreatic insufficiency is typically managed in the outpatient setting as testing and treatment does not require hospitalization. In very severe cases of malnutrition, patients may be hospitalized for enteral nutrition. The diagnostic testing does not require hospitalization, including the 72 hour fecal fat test if ordered.

C. When is the Patient Ready for Discharge.

The patient can be discharged if he is able to tolerate the oral pancreatic enzymes and oral diet and if he is not significantly dehydrated or weak due to the steatorrhea.

D. Arranging for Clinic Follow-up.

Close follow-up is needed to determine response to pancreatic enzyme replacement therapy as the dosage may need to be titrated.

1. When should clinic follow up be arranged and with whom.

Patients should be followed as an outpatient in a Gastroenterology or Pancreas (if available) clinic in 2-3 weeks after discharge. Patient with associated pain may benefit from consultation with pain clinic specialists.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

Fecal elastase to determine if enzyme replacement therapy is adequate.

E. Placement Considerations.

Pancreatic insufficiency is rarely a cause of severe debilitation. However, some of the underlying etiologies (i.e. malignancy, recent surgeries) may result in the need for skilled nursing care.

F. Prognosis and Patient Counseling.

The prognosis is generally good with compliance of pancreatic enzyme supplementation. Patients need counselling and education about the right way to take enzymes and titration of doses according to symptoms.

All patients should be counselled to avoid alcohol and tobacco.

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

Counsel patients about the most common causes and adjustments to be made for treatment failure as below:

Check patient compliance with medical therapy and ensure patients understand the correct timing for enzyme replacement therapy (i.e. 1/2 dose at start of meal and 1/2 dose during the meal).

Patients should be referred to a dietician/nutritionist to discuss appropriate dietary modifications.

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